Substituted 2-(benzenesulfonamido)-pyrimidines

ABSTRACT

wherein R1, R2, R3 and n have the same meanings as defined above, with a sulfonamide compound of the formula (III), (III) wherein R4 has the same meaning as defined above and X is a halogen atom or a reactive group capable of forming a -SO2NHgroup, in the absence or presence of a solvent, and in the presence of an acylation catalyst.   wherein R1, R3 and R4 are a hydrogen atom, a lower alkyl group having one to five carbon atoms or a halogen atom; R2 is a hydrogen atom or a lower alkyl group having one to five carbon atoms; n is 0 or 1. The sulfonamide derivatives have potent blood sugar lowering activity and are prepared by reacting a pyrimidine compound of the formula (II),   Novel sulfonamide derivatives having a pyrimidine ring, represented by the formula (I),

United States Patent Saikawa et al.

I SUBSTITUTED 2- (BENZENESULFONAMIDO)- PYRIMIDINES [72] inventors: lsamu Salkawa; Yasumasa Matubara; Takako Hori, all of Toyama,

Japan [73] Assignee: Toyama Chemical Co., Ltd., Tokyo,

Japan [22] Filed: March 2, 1970 21 Appl. Na; 15,951

[52] US. Cl. ....260l240 D, 260/256.4 N, 260/543 R,

Gutsche et al., Arzneimittel-Forsch 14, 373- 6 (1964).

Primary Examiner-Henry R. Jiles Assistant Examiner-G. Thomas Todd Attorney-Waters, Roditi, Schwartz & Nissen [57] Novelsulfonamide derivatives having a pyrimidine ns IPPIE E/ t 7 21/ h f rma 12.

j of forming a -SO, Nl-I group,

[ Sept. 26, 1972 (admin-QR, I! I (I) wherein R,, R and R, are a hydrogen atom, a lower alkyl group having one to five carbon atoms or a halogen atom; R is a hydrogen atom or a lower alkyl group having one to five carbon atoms; n is 0 or 1. The sulfonamide derivatives have potent blood sugar lowering activity and are prepared by reacting a wherein R R R and n have the same meanings as defined above, with a sulfonamide compound of the fBEBE ME lZ R -U- s 02X wherein R, has the same meaning as defined "Abbie and X is a halogen atom or a reactive group capable in the absence or presence 0 a solven and In the presence of an acylation catalyst.

7 Claims, No Drawings This invention relates to new sulfonamide derivatives -EEL PQWL Q P es w est by the time wherein R R and R are a hydrogen atom, a straightor branched-chain lower alkyl group having one to five carbon atoms such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, n-amyl or isoarnyl group, or a halogen atom such as fluorine, chlorine, bromine or iodine atom; R, is a hydrogen atom, or a straightor branchedchain lower alkyl group having one to five carbon atoms such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, n-amyl or isoamyl group; and n is an integer of or l.

The sulfonamide derivatives represented by the formula (I) are novel and possess potent blood sugar lowering activity.

One object of the present invention is to provide novel sulfonamide derivatives represented by the formula (I) useful as a blood sugar lowering agent.

Another object of the present invention is to provide a process for producing said sulfonamide derivatives represented by the formula (I) by reacting a Z-aminopyrimidine compound represented by the formula Il wherein R R R and n have the same meanings as defined above, with a benzenesulfonyl compound of the formula ill (III) wherein 11,1135 the same meanings as defined above and X is a halogen atom such as chlorine or bromine atom or a reactive group capable of forming SO,NH

crystals are rapidly precipitated. After completion of the reaction, the crystals may be separated from the reaction mixture by means of a conventional method. For example, the reaction mixture is cooled to obtain the desired product in the form of precipitates, then the product is filtered, washed and dried. The crude product may be recrystallized with an organic solvent such as ethylene glycol monomethylether, dimethylformarnide or the like.

wherein R, has the same meaning as defined above, with a phenylaldehyde compound having the formula wherein R R and n have the same meanings as defined above, in acetic acid in the presence of sulfuric acid.

The pharmacological test of some typical compounds of the present invention represented by the formula l) are studied as follows.

Alloxan monohydrate dissolved in distilled water was intravenously injected at the dosage of mg/kg to the tail vein of mice weighing 20 25 g.

At the 7th day after administration of alloxan, 0.02 milliliter of blood was taken by capillary from the venous plexus of eyeground of the mice abstained from food for 16 hours at the certain intervals before and after administration of the compound to be tested. In

the above experiment the compound was administered peritoneally at the dosage of mg/kg. The blood sugar titer was determined and the rate of decrease of blood sugar was calculated.

TABLE 1 Compound Rate of tall 01 blood sugar concentration (percent) cH=oH-cH=cH--om EXAMPLE 1 Preparation of 2amino-S-bromo-4-styryl-pyrimidine 2.95 g. of 2-amino-4-methyl-4-bromopyrimidine was dissolved in ml. of glacial acetic acid, and to this solution, 6 ml. of cone. sulfuric acid was added under ice-cooling. Then 1.68 g. of benzaldehyde and 2.5 ml. of acetic anhydride were added thereto at 25- 27 C. and the reaction mixture was heated at 50 to 60 C for 8 hours. Yellow crystals precipitated from the reaction mixture were isolated by filtration. The thus obtained crystals were suspended in 90 ml. water and neutralized with aqueous ammonia to obtain crude yellow crystals melting at 149 l50 C. Yield: 3 g. (69 percent). Recrystallization with ethanol to obtain yellow crystals in needle fonn, melting at 151 153 C.

Elemental analysis: c H N Br: Calcd.: C, 52.19 H, 3.65 Found C, 51.94 H, 3.89

EXAMPLE 2 Preparation of 2-amino-4-(4-phenyl-l,3-butadienyl)-pyrimidine.

1.0 g. of 2amino-4-methylpyrimidine was dissolved in 10 m1. of glacial acetic acid, and to this solution, 2 ml. of cone. sulfuric acid, 1.45 g. of cinnamaldehyde and 0.9 ml. of acetic anhydride were added and heated at 55 60 C. for l hour, reddish-violet crystals were precipitated. The reaction mixture was kept at the same temperature for another 6 hours. Then the reaction mixture was cooled and the crystals were isolated by filtration and washed with acetic acid. The thus ob tained crystals were suspended in water and made alkaline with aqueous ammonia to obtained crude yellow crystals. Yield: 1.0 g. (49 percent). Recrystallization from ethanol produced yellow crystals in the form of plates, melting at 196 197 C.

Elemental analysis: C H N Calcd.: C, 75.31 H, 5.87

Found C, 75.39 H, 5.87

EXAMPLE 3 Preparation 1 of 2-amino-5-methyl-4-(4-phenyl-1 ,3- butadienyl)-pyrimidine 2.0 g. of 2-amino-4,5-dimethylpyrimidine was dissolved in 20 ml. of glacial acetic acid, and to this solution,'4 m1. of conc. sulfuric acid was added under icecooling. Sulfuric acid salt of 2-amino-4,5-dimethylpyrimidine in white color was precipitated in the mixture. 2.2 g. of cinnamaldehyde was added thereto dropwise at room temperature and the reaction mixture was heated at 50 55 C. for 12 hours. Crystals precipitated in the reaction mixture were isolated by filtration, suspended in water and made alkaline with aqueous ammonia to obtain crude yellow crystals, melting at 169- 170 C. Yield: 1.4 g. (36.3 percent). Recrystallization from aqueous ethanol produced yellow crystals in the from of prisms, melting at 175 176 C.

Elemental analysis: C H N z Calcd.: C, 75.92 H, 6.37

Found C, 76.17 H, 6.47

EXAMPLE 4 Preparation of 2-amino-5-methyl-4[4-(4- methylphenyl )-l ,3-butadienyl1-pyrimidine.

5.0 g. of 2-amino-4,5-dimethylpyrimidine was dissolved in 45 ml. of glacial acetic acid, and to this solution ml. of conc. sulfuric acid was added under icecooling. Then, 6.5 g. of p-methylcinnamaldehyde and 4.5 ml. of acetic anhydride were added thereto at room temperature, and the reaction was carried out at 55 60 C. for 8 hours. Crystals precipitated in the reaction mixture were isolated by filtration, suspended in water and made alkaline with aqueous ammonia to obtain 2.5 g. (24.7 percent) of crude yellow crystals. Recrystallization from aqueous ethanol produced yellow crystals in the form of plates, melting at 179 181 C.

Elemental analysis: C H N Calcd.: C, 76.46 H, 6.82

' Found C, 76.23 H, 7.12

EXAMPLE 5 Preparation of 2-amino-4-[3-methyl-4-(4- chlorophenyl l ,3-butadienyl ]-pyrimidine.

1.0 g. of 2-amino-4-methylpyrimidine was dissolved in 10 ml. of glacial acetic acid, and to this solution 2 ml. of conc. sulfuric acid was added to obtain the sulfuric acid salt of 2-amino-4-methylpyrimidine as a white precipitate in the mixture. Then 0.9 ml. of acetic anhydride and 1.5 g. of 2-methyl-p-chlorocinnamaldehyde were added thereto at room temperature, and the reaction was carried out at 50 55 C. for 7.5 hours. Crystals precipitated in the reaction mixture were isolated by filtration, suspended in water and made alkaline with aqueous ammonia to produce crude yellow crystals melting at 176 177.5 C. Yield: 0.76 g. (30.4 percent). Recrystallization from methanol produced pale yellow crystals in the form of prisms, melting at 179 180 C.

Similar to the method as described in Example 1, 2-

amino-pyrimidine compounds were obtained as shown in Table 2.

TABLE 2 Melting Appearance of crystals point yield R n R, R (C Color Form H 0 CH 209-2092 Pale yellow Prism 80.0 H 0 Cl l79-|79.2 Pale yellow Plate 71.0 H 1 CH H 151-152 Pale yellow Needle 38.0 H 1 CH Cl 179-180 Pale yellow Prism 30.4 H 1 CH Br 193-194 Pale yellow Rhombohedron 29.4 H 1 CH CH 158-161 Pale Yellow Plate 13.0 H l C,H,, Br 164-166 Yellow Brown Prism 31.4 CH, 0 H 152-153 Pale yellow Prism 86.0 CH, 0 CH -173 Yellow Prism 90.0 CH, 1 H H -176 Yellow Prism 36.3 CH, 1 CH CH 170-173 Yellow Prism 12.1 CH, 1 CH H 184-185 Yellow Plate 41.4 Br 0 H 198-1982 Yellow Needle 69.0 Br 0 Br 188-189 Yellow Needle 77.8

EXAMPLE 6 Preparation of 2-(p-toluenesulfonamido)-4-styrylpyrimidine cH=oH- N Hac--s02NH- EXAMPLE 7 Preparation of 2(p toluenesulfonamido)-5-bromo-4- styrylpyrimidine EXAMPLE 8 Preparation of 2-(benzenesulfonamido)-4-(4-phenyll ,3-butadienyl)-pyrimidine.

0.7 g. of 2-amino-4-(4-phenyl-l,3-butadienyl)- pyrimidine, 2ml. of pyridine and 0.61 g. of benzene-sulfonylchloride were mixed and reacted at 90 100 C. for 4 hours. Crystals precipitated in the reaction mixture were isolated by filtration and washed with water and methanol to give crude yellow crystals, melting at 276 277 C. Yield: 0.87 g. (76.5 Recrystallization from ethylene glycol monomethylether produced yellow crystals in the form of prisms, melting at 285 -286 C.

Elemental analysis: C, H, O N S Calcd.: C, 64.08 H, 4.48

Found C, 64.24 H, 4.65

EXAMPLE 9 Preparation of 2-(p-toluenesulfonamido)-5-methyl-4 -(4-phenyll ,3-butadienyl)-pyrimidine 0.35 g. of 2-amino-5-methyl-4-(4phenyl-1,3-butadienyl)-pyrimidine, 0.8 ml. of pyridine and 0.31 g. of p-toluenesulfonylchloride were mixed and reacted at 90 100 C. for 6 hours. After cooling the reaction mixture, crystals precipitated in the mixture were isoluted by filtration and washed with water and acetone to give crude yellow crystals. melting at 274 275 C. Yield; 0.38 g. (65.6 percent). Recrystallization from dimcthylformamide produced yellow crystals in the form 8 of prisms, melting at 278 279 C. Elemental analysis: C H O N S Calcd.: C, 67.49 H, 5.41 Found C, 67.40 H, 5.56

EXAMPLE 10 Preparation of 2-(benzenesulfonamido)-5-methyl-4- [4-(4-methylphenyl l ,3-butadienyl ]-pyrimidine.

0.7 g. of 2-amin0-5-methyl-4-[4-(4-methylphenyl)- l,3-butadienyl1-pyrimidine, 2 ml. of pyridine and 0.54 g. of benzenesulfonyl chloride were mixed and reacted at 90 l00 C. for 6.5 hours. After cooling the reaction mixture, crystals precipitated in the mixture were isolated by filtration and washed with methanol to give crude yellow crystals. Yield: 0.65 g. (58.5 percent). Recrystallization from ethylene glycol monomethylether produced yellow crystals in the form of needles, melting at 271 273 C.

Elemental analysis: czzl'izioz s Calcd.: C, 67.49 H, 5.4l Found: C, 67.37 H, 5.47

EXAMPLE 1 l Preparation of 2-(benzenesulfonamide)-4-[3-methyl- 4-(4-chlorophenyl)-l ,3 butadienyu yrimidine.

0.4 g. of 2-amino-4-[3-methyl-4-(4-chlorophenyl)- l,3-butadienyl]pyrimidine, 0.5 ml. of dimethyl- 40 aniline and 0.25 g. of benzenesulfonyl chloride were mixed and reacted at 90-100 C. for 5.5 hours. After cooling the reaction mixture, crystals precipitated in the mixture were isolated by filtration and washed with water and methanol to give crude yellow crystals melting at 257-260 C. Yield: 0.47 g. (70%). Recrystallization from ethylene glycol monomethylether produced yellow crystals in the form of prisms, melting at 274275 C.

Elemental analysis: C H O N CIS Calcd.: C, 61.23 H, 4.40

Found C, 61.53 H, 4,60

Similar to the method as described in Example 6,2- sulfonamido-4-substituted-pyrimidine derivatives were obtained as shown in Table 3.

Table 3 Melting Appearance of crystals H .CH, 279-280 yellow prism 63.5 CH, H Cl 292-294 paleyellow prism 76.2 CI 0 H H 283-285 yellow needle 85.5 Br 0 H H 288-289 yellow "needle 7 69.3 Br 0"- H j CH, 284-285 yellow needle f 74.3 B; 0 1 H '.'l p l-302 yellow needle 91.5 H l H H CH, 264-265 ye ow prism 69.3 H 1- H vH 285-286 yellow prism 67.3 H 1 CH H C] 254-255 yellow 'pnsm 32.5 Cl l CH, H CH3 253-254.5 yellow needle 64.0 CI 1 CH, H Cl 245-246 yellow needle 58.0 Br 1 CH, H H 265-266 yellow granular 64.5 Br 1 CH, H CH4 252-253 yellow needle 67.0 CH3 1 CH H CH; 239-240 yellow needle 43.! Br I CzHs H CH, 259-260 yellow' plate 36.4 H 0 CH3 H 289-290 pale yellow prism 66.2 H 0 CH; CH, 276-277 pale yellow plate 57.8 H 0 CH; Cl 280-282 yellow needle 80.0 CH3 0 CH; H 302-305 pale yellow prism 5 L8 CH 0 CH; CH, 298-300 pale yellow prism 59.5 H l H CH: H 293-294 yellow prism 49.0 H 1 H CH3 CH 278-279 yellow prism 65.6 CH3 1 H CH H 277-279 yellow needle 58.5 CH; 1 H CH CH3 272-274 yellow prism 59.2 H 1 CH; CH1 CH3 243-245, pale yellow needle 69.6 CH 1 CH, CH; H 237-239 pale yellow fiberous 18.7 CH3 1 CH: CH; CH; 220-223 yellowish powder 53.4

- brown H 0 Br CHI 265-266 yellowish prism 49.]

- l I white Br 0 Br CH3 over3l5 pale yellow prism 85.5 Br 0 CH CH3 311-312 yellow prism 65.2

What is clalmed 1s:

1. A novel sulfonamide pyrimidine derivative of the formula (I),

wherein R R R are a hydrogen atom, a straightor branched-chain lower alkyl 'group'having one to five carbon atoms such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, n-amyl or isoamyl groups, or a halogen atom such as fluorine, chlorine, bromine or iodine atom; R is a hydrogen atom straightor branched-chain lower alkyl group having one to five carbon atoms n is an integer of 0 or 1. 2. 2-(p-Toluenesulfonamide)-4-styryl-pyrimidine. 3. 2-(p-Toluenesulfonamide)-5-bromo-4-styrylpyrimidine. 

2. 2-(p-Toluenesulfonamide)-4-styryl-pyrimidine.
 3. 2-(p-Toluenesulfonamide)-5-bromo-4-styryl-pyrimidine.
 4. 2-Benzenesulfonamido-4-(4-phenyl-1,3-butadienyl)-pyrimidine.
 5. 2-(p-Toluenesulfonamido)-5-methyl-4-(phenyl-1,3-butadienyl)-pyrimidine.
 6. 2-Benzenesulfonamido-5-methyl-4-(4-(4-methylphenyl)-1,3-butadienyl) -pyrimidine.
 7. 2-Benzenesulfonamido-4-(3-methyl-4-(4-chlorophenyl)-1,3-butadienyl) -pyrimidine. 